Pyrrolidine sulfonamides

ABSTRACT

The present invention relates to pyrrolidine sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists.

FIELD OF THE INVENTION

[0001] The present invention relates to pyrrolidine sulfonamides,pharmaceutical compositions containing them and their use as urotensinII antagonists

BACKGROUND OF THE INVENTION

[0002] The integrated control of cardiovascular homeostasis is achievedthrough a combination of both direct neuronal control and systemicneurohormonal activation. Although the resultant release of bothcontractile and relaxant factors is normally under stringent regulation,an aberration in this status quo can result in cardiohemodynamicdysfunction with pathological consequences.

[0003] The principal mammalian vasoactive factors that comprise thisneurohumoral axis, namely angiotensin-II, endothelin-1, norepinephrine,all function via an interaction with specific G-protein coupledreceptors (GPCR). Urotensin-II, represents a novel member of thisneurohumoral axis.

[0004] In the fish, this peptide has significant hemodynamic andendocrine actions in diverse end-organ systems and tissues:

[0005] smooth muscle contraction

[0006] both vascular and non-vascular in origin including smooth musclepreparations from the gastrointestinal tract and genitourinary tract.Both pressor and depressor activity has been described upon systemicadministration of exogenous peptide

[0007] osmoregulation:

[0008] effects which include the modulation of transepithelial ion (Na⁺,Cl) transport. Although a diuretic effect has been described, such aneffect is postulated to be secondary to direct renovascular effects(elevated GFR)

[0009] metabolism:

[0010] urotensin-II influences prolactin secretion and exhibits alipolytic effect in fish (activating triacylglycerol lipase resulting inthe mobilization of non-esterified free fatty acids)

[0011] (Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021;Conlon, et. al. J. Exp. Zool. 1996, 275, 226.)

[0012] In studies with human Urotensin-II it was found that it:

[0013] was an extremely potent and efficacious vasoconstrictor

[0014] exhibited sustained contractile activity that was extremelyresistant to wash out

[0015] had detrimental effects on cardiac performance (myocardialcontractility)

[0016] Human Urotensin-II was assessed for contractile activity in therat-isolated aorta and was shown to be the most potent contractileagonist identified to date. Based on the in vitro pharmacology and in:vivo hemodynamic profile of human Urotensin-II it plays a pathologicalrole in cardiovascular diseases characterized by excessive or abnormalvasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999,401, 282; Douglas & Ohlstein (2001). Trends Cardiovasc. Med., 10: inpress). Compounds that antagonize the Urotensin-II receptor may beuseful in the treatment of congestive heart failure, stroke, ischemicheart disease (angina, myocardial ischemia), cardiac arrhythmia,hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonaryfibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay D WP, Luttmann M A, Douglas S A: 2000, Br J Pharmacol: 131; 10-12)neurogenic inflammation and metabolic vasculopathies all of which arecharacterized by abnormal vasoconstriction and/or myocardialdysfunction. Since U-II and GPR14 are both expressed within themammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may beuseful in the treatment of addiction, schizophrenia, cognitivedisorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain,migraine, and neuromuscular function. Functional U-II receptors areexpressed in rhabdomyosarcomas cell lines and therefore may haveoncological indications. Urotensin may also be implicated in variousmetabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282,Nothacker et al., Nature Cell Biology 1: 383-385, 1999) and in variousgastrointestinal disorders, bone, cartilage, and joint disorders (e.g.arthritis and osteoporosis); and genito-urinary disorders. Therefore,these compounds may be useful for the prevention (treatment) of gastricreflux, gastric motility and ulcers, arthritis, osteoporosis and urinaryincontinence.

SUMMARY OF THE INVENTION

[0017] In one aspect this invention provides for pyrrolidinesulfonamides and pharmaceutical compositions containing them.

[0018] In a second aspect, this invention provides for the use ofpyrrolidine sulfonamides as antagonists of urotensin II, and asinhibitors of urotensin II.

[0019] In another aspect, this invention provides for the use ofpyrrolidine sulfonamides for treating conditions associated withurotensin II imbalance.

[0020] In yet another aspect, this invention provides for the use ofpyrrolidine sulfonamides for the treatment of congestive heart failure,stroke, ischemic heart disease (angina, myocardial ischemia), cardiacarrhythmia, hypertension (essential and pulmonary), COPD, restenosis,asthma, neurogenic inflammation, migraine, metabolic vasculopathies,bone/cartilage/joint diseases, arthritis and other inflammatorydiseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atherosclerosis,dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimersdisease, impulsivity, anxiety, stress, depression, pain, neuromuscularfunction, diabetes, gastric reflux, gastric motility disorders, ulcersand genitourinary diseases.

[0021] The urotensin antagonist may be administered alone or inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, A-II receptorantagonists, vasopeptidase inhibitors, diuretics, digoxin, and dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists.

[0022] Other aspects and advantages of the present invention aredescribed further in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention provides for compounds of Formula (I):

[0024] wherein:

[0025] R₂ is benzimidazolyl, quinolinyl, benzofuranyl, napthyl, indolyl,or benzothiophenyl, phenyl, furanyl, thienyl, or pyridyl substituted orunsubstituted by one, two or three halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, ormethylenedioxy groups;

[0026] R₁ is C₁₋₆ alkyl, benzyl, or (CH₂)_(n)—C(O)NH₂; wherein thebenzyl may be unsubstituted or substituted by one or two C₁₋₆ alkyl,halogen, C₁₋₆ alkoxy, or methylenedioxy groups;

[0027] X₁ and X₂ are independently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃alkoxy, nitro, CF₃, or CN;

[0028] n is 1, 2, or 3;

[0029] m is 1, 2 or 3;

[0030] or a pharmaceutically acceptable salt thereof.

[0031] When used herein, the term “alkyl” includes all straight chainand branched isomers. Representative examples thereof include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl,n-pentyl and n-hexyl.

[0032] When used herein, the terms ‘halogen’ and ‘halo’ includefluorine, chlorine, bromine and iodine and fluoro, chloro, bromo andiodo, respectively.

[0033] The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeform. All of these compounds and their diastereoisomers are contemplatedto be within the scope of the present invention.

[0034] Preferrably:

[0035] m is 1 or 2;

[0036] R₁ is isobutyl;

[0037] R₂ is benzothiopheneyl;

[0038] X₁ is hydrogen, 3-Bromo, or 3-Chloro; and

[0039] X₂ is hydrogen or 5-Chloro.

[0040] Preferred Compounds are:

[0041] Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-chloro-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide

[0042] Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-bromo-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide

[0043] Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-chloro-4-((S)-pyrrolidin-3-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide

[0044] Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-bromo-4-((S)-pyrrolidin-3-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide

[0045] Benzo[b]thiophene-2-carboxylic acid[(S)-3-methyl-1-(2-{4-[4-(piperidinyloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-butyl]-amide

[0046] Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3,5-dichloro-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide

[0047] Compounds of Formula (I) may be prepared as set forth in scheme1.

[0048] Conditions: a) tert-butylchlorodiphenyl silane, triethylamine,CH₂Cl₂, 50° C.; b) 2-nitrobenzenesulfonyl chloride, 0° C.-rt; c) 4 M HClin 1,4-dioxane, rt; d) 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde(DMHB resin), Na(OAc)₃BH, diisopropylethylamine, 1% acetic acid in1-methyl-2-pyrrolidinone, rt; e) Fmoc-HNCH(R₁)COOH,1,3-diisopropylcarbodiimide, 1-hydroxy-7-azabenzotriazole,1-methyl-2-pyrrolidinone, rt; f) 20% piperidine in1-methyl-2-pyrrolidinone, rt; g) R₂COOH, 1,3-diisopropylcarbodiimide,1-hydroxy-7-azabenzotriazole, 1-methyl-2-pyrrolidinone, rt; h) K₂CO₃,PhSH, 1-methyl-2-pyrrolidinone, rt; i)(X₁)(X₂)-4-hydroxy-benzenesulfonyl chloride, 1,2-dichloroethane,1-methyl-2-pyrrolidinone, rt; j) potassium trimethylsilanolate,tetrahydrofuran, rt; k) R₂OH, diisopropyl azodicarboxylate, PPh₃,tetrahydrofuran, −78° C.-rt; 1) 50% trifluoroacetic acid in1,2-dichloroethane, rt.

[0049] As shown in scheme 1, resin-bound amine 3 was prepared byreductive amination of 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde(DMHB resin) piperazinyl-ethylamine HCl salt 2 which was prepared from1-(2-aminoethyl)piperazine (1). Reactions of resin-bound amine 3 withvarious amino acids, followed by removal of the protecting group,resulted in the corresponding resin-bound amines 4. Amines 4 were thenreacted with various acids to afford the corresponding resin-boundamides 5. Resin-bound amides 5 were subsequently treated with potassiumcarbonate and thiophenol to give secondary amines 6. Sulfonylation ofresin-bound amines 6 with various hydroxy-benzenesulfonyl chlorides,followed by treatment with potassium trimethylsilanolate, producedresin-bound phenols 7. Phenols 7 were then reacted with various alcoholsin the presence of triphenylphosphine and diisopropyl azodicarboxylateto give the corresponding resin-bound phenol ethers which were treatedwith 50% trifluoroacetic acid in 1,2-dichloroethane to afford targetedcompounds 8.

[0050] With appropriate manipulation, including the use of alternativenitrogen protecting group(s), the synthesis of the remaining compoundsof Formula (I) was accomplished by methods analogous to those above andto those described in the Experimental section.

[0051] In order to use a compound of the Formula (I) or apharmaceutically acceptable salt thereof for the treatment of humans andother mammals it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

[0052] Compounds of Formula (1) and their pharmaceutically acceptablesalts may be administered in a standard manner for the treatment of theindicated diseases, for example orally, parenterally, sub-lingually,transdermally, rectally, via inhalation or via buccal administration.

[0053] Compounds of Formula (I) and their pharmaceutically acceptablesalts which are active when given orally can be formulated as syrups,tablets, capsules and lozenges. A syrup formulation will generallyconsist of a suspension or solution of the compound or salt in a liquidcarrier for example, ethanol, peanut oil, olive oil, glycerine or waterwith a flavoring or coloring agent. Where the composition is in the formof a tablet, any pharmaceutical carrier routinely used for preparingsolid formulations may be used. Examples of such carriers includemagnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia,stearic acid, starch, lactose and sucrose. Where the composition is inthe form of a capsule, any routine encapsulation is suitable, forexample using the aforementioned carriers in a hard gelatin capsuleshell. Where the composition is in the form of a soft gelatin shellcapsule any pharmaceutical carrier routinely used for preparingdispersions or suspensions may be considered, for example aqueous gums,celluloses, silicates or oils and are incorporated in a soft gelatincapsule shell.

[0054] Typical parenteral compositions consist of a solution orsuspension of the compound or salt in a sterile aqueous or non-aqueouscarrier optionally containing a parenterally acceptable oil, for examplepolyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, orsesame oil.

[0055] Typical compositions for inhalation are in the form of asolution, suspension or emulsion that may be administered as a drypowder or in the form of an aerosol using a conventional propellant suchas dichlorodifluoromethane or trichlorofluoromethane.

[0056] A typical suppository formulation comprises a compound of Formula(1) or a pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent, forexample polymeric glycols, gelatins, cocoa-butter or other low meltingvegetable waxes or fats or their synthetic analogues.

[0057] Typical transdermal formulations comprise a conventional aqueousor non-aqueous vehicle, for example a cream, ointment, lotion or pasteor are in the form of a medicated plaster, patch or membrane.

[0058] Preferably the composition is in unit dosage form, for example atablet, capsule or metered aerosol dose, so that the patient mayadminister to themselves a single dose.

[0059] Each dosage unit for oral administration contains suitably from0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and eachdosage unit for parenteral administration contains suitably from 0.1 mgto 100 mg, of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof calculated as the free acid. Each dosage unit forintranasal administration contains suitably 1-400 mg and preferably 10to 200 mg per person. A topical formulation contains suitably 0.01 to1.0% of a compound of Formula (I).

[0060] The daily dosage regimen for oral administration is suitablyabout 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (1) or apharmaceutically acceptable salt thereof calculated as the free acid.The daily dosage regimen for parenteral administration is suitably about0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (1) or apharmaceutically acceptable salt thereof calculated as the free acid.The daily dosage regimen for intranasal administration and oralinhalation is suitably about 10 to about 500 mg/person. The activeingredient may be administered from 1 to 6 times a day, sufficient toexhibit the desired activity.

[0061] These sulphonamide analogs may be used for the treatment ofcongestive heart failure, stroke, ischemic heart disease (angina,myocardial ischemia), cardiac arrhythmia, hypertension (essential andpulmonary), COPD, restenosis, asthma, neurogenic inflammation andmetabolic vasculopathies, addiction, schizophrenia, impulsivity,anxiety, stress, depression, neuromuscular function, and diabetes.

[0062] The urotensin antagonist may be administered alone or inconjunction with one or more other therapeutic agents, said agents beingselected from the group consisting of endothelin receptor antagonists,angiotensin converting enzyme (ACE) inhibitors, vasopeptidaseinhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptorand α₁-adrenoceptor antagonists.

[0063] No unacceptable toxicological effects are expected when compoundsof the invention are administered in accordance with the presentinvention.

[0064] The biological activity of the compounds of Formula (I) aredemonstrated by the following tests:

[0065] Radioligand Binding:

[0066] HEK-293 cell membranes containing stable cloned human and ratGPR-14 (20 ug/assay) were incubated with 200 pM [125I] h-U-II (200Ci/mmol⁻¹ in the presence of increasing concentrations of test compoundsin DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mMTris-HCl, 5 mM MgCl2). Incubation was done for 30 minutes at roomtemperature followed by filtration GF/B filters with Brandel cellharvester. ¹²⁵I labeled U-II binding was quantitated by gamma counting.Nonspecific binding was defined by ¹²⁵I U-II binding in the presence of100 nM of unlabeled human U-II. Analysis of the data was performed bynonlinear least square fitting.

[0067] Ca²⁺-Mobilization:

[0068] A microtitre plate based Ca²⁺-mobilization FLIPR assay (MolecularDevices, Sunnyvale, Calif.) was used for the functional identificationof the ligand activating HEK-293 cells expressing (stable) recombinantGPR-14. The day following transfection, cells were plated in apoly-D-lysine coated 96 well black/clear plates. After 18-24 hours themedia was aspirated and Fluo 3AM-loaded cells were exposed to variousconcentrations (10 nM to 30 uM) of test compounds followed by h-U-II.After initiation of the assay, fluorescence was read every second forone minute and then every 3 seconds for the following one minute. Theinhibitory concentration at 50% (IC50) was calculated for various testcompounds.

[0069] Inositol Phosphates Assays:

[0070] HEK-293-GPR14 cells in T150 flask were prelabeled overnight with1 uCi myo-[³H] inositol per ml of inositol free Dulbecco's modifiedEagel's medium. After labeling, the cells were washed twice withDulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBScontaining 10 mM LiCl for 10 min at 37° C. The experiment was initiatedby the addition of increasing concentrations of h-U-II (1 pM to 1 μM) inthe absence and presence of three different concentrations (0.3, 1 and10 uM) of test compounds and the incubation continued for an additional5 min at 37° C. after which the reaction was terminated by the additionof 10% (final concentration) trichloroacetic acid and centrifugation.The supernatants were neutralized with 100 ul of 1M Trizma base and theinositol phosphates were separated on AG 1-X8 columns (0.8 ml packed,100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8ml of 200 mM ammonium formate. Combined inositol di and tris phosphatewas eluted with 4 ml of 1M ammonium formate/0.1 M formic acid. Elutedfractions were counted in beta scintillation counter. Based on shiftfrom the control curve K_(B) was calculated.

[0071] Activity for the compounds of this invention range from(radioligand binding assay): Ki=5 nM−10000 nM (example 5 Ki=1400 nM)

[0072] The following Examples are illustrative but not limitingembodiments of the present invention.

Example 1

[0073] Preparation of Benzo[b]thiophene-2-carboxylic Acid[(S)-3-methyl-1-(2-{4-[4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-butyl]-amide

[0074] a) 2-[4-(2-Nitro-benzenesulfonyl)-piperazin-1-yl]-ethylamine HClSalt

[0075] To a solution of 100 mL (760.8 mmol) of1-(2-aminoethyl)piperazine in 636 mL (4.56 mol) of triethylamine and 800mL of anhydrous CH₂Cl₂ at rt under argon was added 198 mL (760.8 mmol)of tert-butylchlorodiphenyl silane. The mixture was refluxed at 50° C.for 2.5 h. The mixture was then cooled to 0° C. 168.6 g (760.8 mmol) of2nitrobenzenesulfonyl chloride was added to the mixture in 3 portions.The resulting mixture was stirred at 0° C. for 1 h and warmed to rt andstirred at rt for 16 h. The mixture was diluted with 1.5 L of CH₂Cl₂ andpoured into 1 L of 1 M NaHCO₃ aqueous solution. After stirring for 15min, the organic layer was separated and washed with 1 L of 1 M NaHCO₃aqueous solution. The resulting organic layer was dried over K₂CO₃ andconcentrated ill vacuo. The residue was dissolved into 400 mL of1,4-dioxane. The solution was concentrated in vacuo to remove theremaining triethylamine.

[0076] The above residue was dissolved in 1 L of anhydrous 1,4-dioxaneand was diluted with 2 L of anhydrous ether. The resulting mixture wastreated with 800 mL of 4 M HCl solution in 1,4-dioxane under argon. Themixture was vigorously stirred at rt under argon for 1 h. The resultingsuspension was filtered. The precipitation was washed 5 times with 500mL portions of anhydrous ether. The resulting solid was dried in vacuumoven for 24 h to yield2-[4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-ethylamine HCl salt as awhite solid (340 g, 80% pure): MS (ESI) 315 [M+H]+(which wascontaminated with 20% of the dinosyl-protected amine HCl salt: MS (ESI)500 [M+H]⁺. It is not necessary to purify the crude product, however,the pure amine HCl salt example 1-a could be obtained viarecrystallization of the crude product in MeOH).

[0077] b) 4-Hydroxybenzenesulfonyl Chloride

[0078] To chlorosulfonic acid (248 mL, 3.37 mol) cooled to −3° C. wasadded dropwise a solution of phenol (70 g, 0.744 mol) in 250 mL ofanhydrous methylene chloride over a period of 1 hour under argon gas.The mixture was warmed to rt over 1 h and was stirred at rt for 1.5 h.The mixture was poured over ice, stirred for 30 min, and was extractedwith methylene chloride (4×2 L). The resulting organic layer was driedover MgSO₄ and concentrated iii vacuo to yield 4-hydroxybenzenesulfonylchloride as a sticky brown solid (41.49 g, 29%): ¹H NMR (400 MHz,d₆-DMSO) δ 7.29-7.38 (d, 2H), 6.58-6.69 (d, 2H).

[0079] c) Benzo[b]thiophene-2-carboxylic acid[(S)-3-methyl-1-(2-{4-[4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-butyl]-amide

[0080] To a mixture of 20.20 g (29.08 mmol, 1.44 mmol) of2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) in 439.4mL of 1% acetic acid in anhydrous 1-methyl-2-pyrrolidinone was added27.42 g (70.8 mmol) of2-[4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-ethylamine HCl salt and25.33 mL (145.4 mmol) of diisopropylethyl amine, followed by addition of30.8 g (145.4 mmol) of sodium triacetoxyborohydride. After the resultingmixture was shaken at rt for 65 h under argon gas, the resin was washedwith CH₂Cl₂/methanol (1:1, 3×400 mL), DMF (3×400 mL), CH₂Cl₂ (1×400 mL)and methanol (2×400 mL). The resulting resin was dried in vacuum oven at35° C. for 24 h. Elemental analysis N: 4.27, S: 5.25.

[0081] To a mixture of 10 g (7.914 mmol, 0.7914 mmol/g) of the aboveresin in 165 mL of anhydrous 1-methyl-2-pyrrolidinone was added 13.985 g(39.57 mmol) of Fmoc-Leu-OH and 1.077 g (7.914 mmol) of1-hydroxy-7-azabenzotriazole, followed by addition of 7.490 mL (47.48mmol) of 1,3-diisopropylcarbodiimide. After the resulting mixture wasshaken at rt for 44 h, the resin was washed with1-methyl-2-pyrrolidinone (3×150 mL), dichloroethane/methanol (1:1, 3×150mL) and methanol (3×150 mL). The resulting resin was dried in vacuumoven at 35° C. for 24 h. An analytical amount of resin was cleaved with50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resultingsolution was concentrated in vacuo: MS (ESI) 621 [M+H]⁺.

[0082] The above resin (7.914 mmol) was treated with 175 mL of 20%piperidine in anhydrous 1-methyl-2-pyrrolidinone solution. After themixture was shaken at rt for 15 min, the solution was drained andanother 175 mL of 20% piperidine in anhydrous 1-methyl-2-pyrrolidinonesolution was added. The mixture was shaken at rt for another 15 min. Thesolution was drained and the resin was washed with1-methyl-2-pyrrolidinone (3×175 mL), CH₂Cl₂/MeOH (1:1, 3×175 mL) andCH₂Cl₂ (3×175 mL). The resulting resin was dried in vacuum oven at 35°C. for 24 h. An analytical amount of resin was cleaved with 50%trifluoroacetic acid in dichloroethane for 2 h at rt. The resultingsolution was concentrated in vacuo: MS (ESI) 399 [M+H]⁺.

[0083] To a mixture of 200 mg (0.1453 mmol, 0.7264 mmol/g) of the abovedry resin in 5 mL of anhydrous 1-methyl-2-pyrrolidinone was added 129.5mg (0.7265 mmol) of benzo[b]thiophene-2-carboxylic acid and 19.8 mg(0.1453 mmol) of 1-hydroxy-7-azabenzotriazole, followed by addition of0.137 mL (0.8718 mmol) of 1,3-diisopropylcarbodiimide. After theresulting mixture was shaken at rt for 48 h, the resin was washed with1-methyl-2-pyrrolidinone (3×10 mL), CH₂Cl₂/MeOH (1:1, 3×10 mL) andCH₂Cl₂ (3×10 mL). The resulting resin was dried in vacuum oven at 35° C.for 24 h. An analytical amount of resin was cleaved with 50%trifluoroacetic acid in dichloroethane for 2 h at rt. The resultingsolution was concentrated in vacuo: MS (ESI) 559 [M+H]⁺.

[0084] To a mixture of 0.1453 mmol of the above dry resin in 6 mL of1-methyl-2-pyrrolidinone was added 200.8 mg (1.453 mmol) of K₂CO₃ and0.0746 mL (0.7265 mmol) of PhSH. After the resulting mixture was shakenat rt for 20 h, the resin was washed with methanol (1×10 mL), H₂O (3×10mL), methanol (1×10 mL), 1-methyl-2-pyrrolidinone (1×10 mL),CH₂Cl₂/methanol (1:1, 3×10 mL) and methanol (3×10 mL). The resultingresin was dried in vacuum oven at 35° C. for 24 h. An analytical amountof resin was cleaved with 50% trifluoroacetic acid in dichloroethane for2 h at rt. The resulting solution was concentrated in vacuo: MS (ESI)747 [2M+H]⁺, 374 [M+H]⁺.

[0085] To a mixture of 0.1453 mmol of the above dry resin in anhydrousdichloroethane/1-methyl-2-pyrrolidinone solution (1:1, 7.5 mL) was added0.2264 mL (2.799 mmol) of pyridine followed by the slow addition of0.5393 g (2.799 mmol) of 4-hydroxybenzenesulfonyl chloride. After theresulting mixture was shaken at rt for 96 h, the resin was washed with1-methyl-2-pyrrolidinone (3×10 mL), dichloroethane/methanol (1:1, 3×10mL), dichloroethane (3×10 mL), methanol (1×10 mL), and dichloroethane(2×10 mL). The resulting resin was dried in vacuum oven at 35° C. for 24h. To a mixture of the dry resin in anhydrous tetrahydrofuran (9.38 mL)was added 0.4713 g (3.674 mmol) of potassium trimethyl silanolate. Afterthe reaction mixture was shaken for 23 h, the resin was washed withtetrahydrofuran (3×10 mL), 1-methyl-2-pyrrolidinone (2×10 mL),tetrahydrofuran (3×10 mL), dichloroethane/methanol (5×10 mL), anddichloroethane (3×10 mL). An analytical amount of resin was cleaved with50% trifluoroacetic acid in dichloroethane for 2 h at rt. The resultingsolution was concentrated in vacuo: MS (ESI) 530 [M+H]⁺.

[0086] To a mixture of 200 mg of the above dry resin in 8.75 mL ofanhydrous tetrahydrofuran was added 443 mg (2.199 mmol) of4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester and 577 mg (2.199mmol) of triphenylphosphine. After the mixture was cooled to −70° C.,433 mL (2.199 mmol) of diisopropyl azodicarboxylate was added to thecold mixture. The resulting mixture was kept at −70° C. for 30 min whileshaking. The mixture was then allowed to warm to 0° C. over 1 h andshaken at rt for 19 h. The resin was washed with tetrahydrofuran (3×10mL), CH₂Cl₂/methanol (1:1, 10×10 mL). The resulting resin was dried invacuum oven at 35° C. for 24 h. The dry resin was treated with 4 mL of50% trifluoroacetic acid in dichloroethane at rt for 2 h. After thecleavage solution was collected, the resin was treated with another 4 mLof 50% trifluoroacetic acid in dichloroethane at rt for 10 min. Thecombined cleavage solutions were concentrated in vacuo. The residue waspurified using a Gilson semi-preparative HPLC system with a YMC ODS-A(C-18) column 50 mm by 20 mm ID, eluting with 10% B to 90% B in 3.2 min,hold for 1 min where A=H₂O (0.1% trifluoroacetic acid) and B=CH₃CN (0.1%trifluoroacetic acid) pumped at 25 mL/min, to producebenzo[b]thiophene-2-carboxylic acid((S)-3-methyl-1-{1-[4-(piperidin-4-yloxy)-benzenesulfonyl]-piperidin-4-ylcarbamoyl}-butyl)-amideas a mono-trifluoroacetic acid salt (white powder, 23.0 mg, 28% over 11steps): MS (ESI) 642 [M+H]⁺.

[0087] Compounds Derived From Scheme 1: MS (ES+) Example R1 R2 R3 X1 X2m/e 2 isobutyl benzothiopheneyl piperidin-4-yl 3-chloro H 676 (M + H) 3isobutyl benzothiopheneyl piperidin-4-yl 3-bromo H 720 (M + H) 4isobutyl benzothiopheneyl piperidin-4-yl 3-chloro 5-chloro 610 (M + H) 5isobutyl benzothiopheneyl pyrrolidin- H H 628 (M + H) 3(R)-yl 6 isobutylbenzothiopheneyl pyrrolidin- 3-chloro H 662 (M + H) 3(R)-yl 7 isobutylbenzothiopheneyl pyrrolidin- 3-bromo H 707 (M + H) 3(R)-yl 8 isobutylbenzothiopheneyl pyrrolidin- 3-chloro 5-chloro 696 (M + H) 3(R)-yl 9isobutyl benzothiopheneyl pyrrolidin- 3-chloro H 662 (M + H) 3(S)-yl 10isobutyl benzothiopheneyl pyrrolidin- 3-bromo H 707 (M + H) 3(S)-yl

Example 11

[0088] Formulations for pharmaceutical use incorporating compounds ofthe present invention can be prepared in various forms and with numerousexcipients. Examples of such formulations are given below.Tablets/Ingredients Per Tablet 1. Active ingredient  40 mg   (Cpd ofForm. I) 2. Corn Starch  20 mg 3. Alginic acid  20 mg 4. Sodium Alginate 20 mg 5. Mg stearate 1.3 mg 2.3 mg

[0089] Procedure for Tablets:

[0090] Step 1: Blend ingredients No. 1, No. 2, No. 3 and No. 4 in asuitable mixer/blender.

[0091] Step 2: Add sufficient water portion-wise to the blend from Step1 with careful mixing after each addition. Such additions of water andmixing until the mass is of a consistency to permit its conversion towet granules.

[0092] Step 3: The wet mass is converted to granules by passing itthrough an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

[0093] Step 4: The wet granules are then dried in an oven at 140° F.(60° C.) until dry.

[0094] Step 5: The dry granules are lubricated with ingredient No. 5.

[0095] Step 6: The lubricated granules are compressed on a suitabletablet press.

[0096] Inhalant Formulation

[0097] A compound of Formula I, (1 mg to 100 mg) is aerosolized from ametered dose inhaler to deliver the desired amount of drug per use.

[0098] Parenteral Formulation

[0099] A pharmaceutical composition for parenteral administration isprepared by dissolving an appropriate amount of a compound of formula Iin polyethylene glycol with heating. This solution is then diluted withwater for injections Ph Eur. (to 100 ml). The solution is thensterilized by filtration through a 0.22 micron membrane filter andsealed in sterile containers.

[0100] The above specification and Examples fully disclose how to makeand use the compounds of the present invention. However, the presentinvention is not limited to the particular embodiments describedhereinabove, but includes all modifications thereof within the scope ofthe following claims. The various references to journals, patents andother publications which are cited herein comprise the state of the artand are incorporated herein by reference as though fully set forth.

What is claimed is:
 1. A compound of Formula (I):

wherein: R₁ is C₁₋₆ alkyl, benzyl, or (CH₂)_(n)—C(O)NH₂; wherein thebenzyl may be unsubstituted or substituted by one or two C₁₋₆ alkyl,halogen, C₁₋₆ alkoxy, or methylenedioxy groups; R₂ is benzimidazolyl,quinolinyl, benzofuranyl, napthyl, indolyl, benzothiophenyl, phenyl,furanyl, thienyl, or pyridyl substituted or unsubstituted by one, two orthree halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, or methylenedioxy groups; X₁ andX₂ are independently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy, nitro,CF₃, or CN; n is 1, 2, or 3; m is 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1 wherein m is 1 or 2;R₁ is isobutyl; R₂ is benzothiopheneyl; X₁ is hydrogen, 3-Bromo, or3-Chloro; and X₂ is hydrogen or 5-Chloro.
 3. A compound of claim 1chosen from the group consisting of: Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-chloro-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-;Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-bromo-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide;Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-chloro-4-((S)-pyrrolidin-3-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide;Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3-bromo-4-((S)-pyrrolidin-3-yloxy)-benzenesulfonyl]-piperazin-1-yl)-ethylcarbamoyl)-3-methyl-butyl]-amide;Benzo[b]thiophene-2-carboxylic acid[(S)-3-methyl-1-(2-{4-[4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-butyl]-amide;and Benzo[b]thiophene-2-carboxylic acid[(S)-1-(2-{4-[3,5-dichloro-4-(piperidin-4-yloxy)-benzenesulfonyl]-piperazin-1-yl}-ethylcarbamoyl)-3-methyl-butyl]-amide.4. A pharmaceutical composition comprising a compound of formula (I) ofclaim 1 and a pharmaceutically acceptable carrier or excipient.
 5. Amethod of treating conditions associated with Urotensin-II imbalance byantagonizing the Urotensin-II receptor which comprises administering toa patient in need thereof, a compound of Formula I of claim
 1. 6. Amethod according to claim 5 wherein the disease is congestive heartfailure, stroke, ischemic heart disease, angina, myocardial ischemia,cardiac arrythmias, essential hypertension, pulmonary hypertension,COPD, restenosis, asthma, neurogenic inflammation metabolicvasculopathies, addiction, schizophrenia, cognitive disorders/Alzheimersdisease, impulsivity, anxiety, stress, depression, neuromuscularfunction, or diabetes.